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Page 6 of 11 Genovesi et al. Vessel Plus 2021;5:50 https://dx.doi.org/10.20517/2574-1209.2021.67

are 99mTc-3,3-diphosphono-1,2propanodicarboxylic acid (99mTc-DPD), 99mTc-hydroxymethylene
diphosphonate (99mTc-HMDP), and 99mTc-pyrophosphate (99mTc-PYP). The first observation of
[37]
99mTc-DPD cardiac uptake in patients with AC was reported in 1977 by Kula et al. . In the following
decades, the number of observations supporting the usefulness of these radiopharmaceuticals for the
diagnosis of CA has progressively increased. In 2005, Perugini et al. demonstrated the high accuracy of
[38]
cardiac retention of 99mTc-DPD in identifying patients with ATTR: cardiac uptake of the
radiopharmaceutical was absent in controls and patients with AL, therefore 99mTc-DPD scintigraphy
identified 100% of ATTR. In the same paper, a score of myocardial uptakes known as the “Perugini score”
was proposed; this score is now widely used in clinical practice and provides a four-point scale, from 0 to 3,
[39]
as described in Figure 1. In a later study performed in a larger population, Rapezzi et al. semi-
quantitatively evaluated myocardial uptake of 99mTc-DPD [heart/total body retention ratio (H/WB)]; with
this approach, the accuracy resulted lower than previously reported as one third of patients with AL
amyloidosis showed mild cardiac uptake of the radiopharmaceutical. By using a semiquantitative cut-off of
moderate to high uptake (Scores 2-3), 99mTc-DPD scintigraphy showed 100% and 88% sensitivity and
specificity, respectively. Cardiac retention of 99mTc-DPD has been shown to correlate with inter-
ventricular septum thickening and the severity of the contractile function impairment ; moreover, a
[40]
marked cardiac retention of the radiopharmaceutical has been associated with a high risk of future cardiac
events and poor prognosis .
[41]
99mTc-PYP is another commonly used radiopharmaceutical for bone imaging which has been shown to be
useful for diagnosing CA. In 1983, Falk et al. evaluated 20 patients with CA and 10 control subjects using
[42]
99mTc-PYP, reporting a high cardiac uptake of the radiopharmaceutical in 9 of 11 patients with
echocardiograms suggestive of amyloidosis and in only 2 patients without pseudohypertrophy. None of the
10 control subjects showed cardiac pyrophosphate uptake, suggesting that 99mTc-PYP scintigraphy could
represent a non-invasive imaging of CA . In a study on a larger sample of patients with a biopsy-proven
[42]
CA (12 AL, 16 ATTR wild-type, and 17 ATTR familial), both the evaluation through a visual score and a
semiquantitative measure of myocardial uptake (heart/contralateral chest activity ratio) correlated with
ventricular wall thicknesses and myocardial mass and were higher in subjects with ATTR. The sensitivity
and specificity of the method were 97% and 100%, respectively .
[43]

[44]
Recently, Cappelli et al. evaluated the diagnostic performance of 99mTc-HMDP in a population of 65
patients with histological diagnosis of cardiac amyloidosis (39 ATTR and 26 AL) and in 20 subjects with
non-amyloidotic ventricular hypertrophy. The visual score imaging evaluation provided a diagnostic
sensitivity of 100% and a specificity of 96%. None of the subjects with non-amyloidotic left ventricular
hypertrophy had significant uptake of the radiopharmaceutical. Using a semiquantitative approach
(heart/total body activity ratio) and a threshold of > 3.3, a diagnostic accuracy of 100% was obtained in the
diagnosis of ATTR. The authors concluded that 99mTc-HMDP scintigraphy can be used in the differential
diagnosis of AC with levels of accuracy comparable to those of other osteophilic radiopharmaceuticals
previously evaluated.

The real milestone study for this method was conducted by Gillmore et al. , who analyzed the
[45]
scintigraphic results obtained with the three available 99mTc-labeled radiopharmaceuticals in more than
1000 patients with suspected AC. Bone scan had a diagnostic sensitivity greater than 99% and a specificity of
86% in identifying cardiac involvement from ATTR, with false positives mostly due to mild uptake patterns
in patients with AL amyloidosis. When considering moderate to high scintigraphic uptake patterns with the
absence of serum and urinary monoclonal protein, a diagnostic specificity and a positive predictive value for
ATTR of 100% were obtained. Therefore, the authors suggested that a positive scintigraphic imaging in